The invention concerns 2-oxo-1-pyrrolidine derivatives and a process for preparing them and their uses. The invention also concerns a process for preparing xcex1-ethyl-2-oxo-1-pyrrolidine acetamide derivatives from unsaturated 2-oxo-1-pyrrolidine derivatives.
Particularly the invention concerns novel intermediates and their use in methods for the preparation of (S)-(xe2x88x92)-xcex1-ethyl-2-oxo-1-pyrrolidine acetamide, which is referred under the International Nonproprietary Name of Levetiracetam, its dextrorotatory enantiomer and related compounds. Levetiracetam is shown as having the following structure: 
Levetiracetam, a laevorotary compound is disclosed as a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system in the European patent No. 162036. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-xcex1-ethyl-2-oxo-1-pyrrolidine acetamide completely lacks activity (A. J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203). Finally, in the European patent application No. 0 645 139 this compound has been disclosed for its axiolytic activity.
The asymmetric carbon atom carries a hydrogen atom (not shown) positioned above the plane of the paper. The preparation of Levetiracetam has been described in the European patent No. 0162 036 and in the British patent No. 2 225 322, both of which are assigned to the assignee of the present invention. The preparation of the dextrorotatory enantiomer (R)-(+)-xcex1-ethyl-2-oxo-1-pyrrolidine acetamide has been described in the European patent No. 0165 919. Nevertheless, these approaches do not fully satisfy the requirements for an industrial process. Therefore, a new approach has been developed via the asymmetric hydrogenation of new precursors.
In one aspect, the invention provides a compound having the general formula (A) and pharmaceutically acceptable salts thereof, 
wherein X is xe2x80x94CONR5R6 or xe2x80x94COOR7 or xe2x80x94COR8 or CN;
R1 is hydrogen or alkyl, aryl, heterocycloalkyl, heteroaryl, halogen, hydroxy, amino, nitro, cyano;
R2, R3, R4, are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfmyl, alkylthio, arylthio, alkyl, alkoxy, oxyester, oxyamido, aryl, arylamino, axyloxy, heterocycloalkyl, heteroaryl, vinyl;
R5, R6, R7 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy; and
R8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycloalkyl, heteroaryl, alkylthio, arylthio.
The term alkyl as used herein, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and contains 1-20 carbon atoms, preferably 1-5 carbon atoms. The alkyl group may optionally be substituted by 1 to 5 substituents independently selected from the group consisting halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, oxyester, oxyamido, heterocycloalkyl, heteroaryl, vinyl, (C1-C5)alkoxy, (C6-C10)aryloxy, (C6-C10)aryl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a group selected from halogen, hydroxy, thiol, amino, nitro, cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d, as used herein, represents an xe2x80x9c(C1-C6)cycloalkylxe2x80x9d as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrolidinyl groups or the same substituted by at least a group selected from halogen, hydroxy, thiol, amino, nitro, cyano.
The term xe2x80x9calkoxyxe2x80x9d, as used herein includes xe2x80x94O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
The term xe2x80x9calkylthioxe2x80x9d as used herein, includes Bakyl groups wherein xe2x80x9calkylxe2x80x9d is defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1, 1-dimethyl-2,2,2-trichloroethyl.
The term xe2x80x9calkylaminoxe2x80x9d as used herein, includes xe2x80x94NHalkyl or xe2x80x94N(alkyl)2 groups wherein xe2x80x9calkylxe2x80x9d is defined above. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group.
The term xe2x80x9carylxe2x80x9d as used herein, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, phenoxy, naphthyl, arylalkyl, benzyl, optionally substituted by 1 to 5 substituents independently selected from the group halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, alkoxycarbonyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, (C1-C6)alkoxy, (C6-C10)aryloxy and (C1-C6)alkyl. The aryl radical consists of 1-3 rings preferably one ring and contains 2-30 carbon atoms preferably 6-10 carbon atoms. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, naphthyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9carylaninoxe2x80x9d as used herein, includes xe2x80x94NHaryl or xe2x80x94N(aryl)2 groups wherein xe2x80x9carylxe2x80x9d is defined above. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9caryloxyxe2x80x9d, as used herein, includes xe2x80x94O-aryl groups wherein xe2x80x9carylxe2x80x9d is defined as above. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9carylthioxe2x80x9d, as used herein, includes aryl groups wherein xe2x80x9carylxe2x80x9d is defined as above. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9chalogenxe2x80x9d, as used herein, includes an atom of Cl, Br, F, I.
The term xe2x80x9chydroxyxe2x80x9d, as used herein, represents a group of the formula xe2x80x94OH.
The term xe2x80x9cthiolxe2x80x9d, as used herein, represents a group of the formula xe2x80x94SH.
The teem xe2x80x9ccyanoxe2x80x9d, as used herein, represents a group of the formula xe2x80x94CN.
The term xe2x80x9critroxe2x80x9d, as used herein, represents a group of the formula xe2x80x94NO2.
The term xe2x80x9caminoxe2x80x9d, as used herein, represents a group of the formula xe2x80x94NH2.
The term xe2x80x9ccarboxyxe2x80x9d, as used herein, represents a group of the formula xe2x80x94COOH.
The term xe2x80x9csulfonic acidxe2x80x9d, as used herein, represents a group of the formula xe2x80x94SO3H.
The term xe2x80x9csulfonamidexe2x80x9d, as used herein, represents a group of the formula xe2x80x94SO2NH2.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, unless otherwise indicated, represents an xe2x80x9carylxe2x80x9d as defined above, having at least one O, S and/or N interrupting the carbocyclic ring structure, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyiimidyl, quinolyl, isoquinolyl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, or benzoxazolyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting hydroxy, halogen, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfmyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, alkoxycarbonyl, oxyester, oxyamido, alkoxycarbonyl, (C1-C5)alkoxy, and (C1-C5)alkyl.
The term xe2x80x9carylalkylxe2x80x9d as used herein represents a group of the formula aryl-(C1-C4 alkyl)-. Preferred arylalkyl groups are, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl, diphenylmethyl, (4-methoxyphenyl)diphenylmethyl.
The term xe2x80x9cacylxe2x80x9d as used herein, represents a radical of carboxylic acid and thus includes groups of the formula alky-COxe2x80x94, aryl-COxe2x80x94, heteroaryl-COxe2x80x94, arylalkyl xe2x80x94COxe2x80x94, wherein the various hydrocarbon radicals are as defined in this section. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9coxyacylxe2x80x9d as used herein, represents a radical of carboxylic acid and thus includes groups of the formula alky-COxe2x80x94Oxe2x80x94, aryl-COxe2x80x94Oxe2x80x94, heteroaryl-COxe2x80x94Oxe2x80x94, arylalkyl-COxe2x80x94O, wherein the various hydrocarbon radicals are as defined in this section. Preferred alky and aryl groups are the same as those defined for the acyl group.
The term xe2x80x9csulfonylxe2x80x9d represents a group of the formula xe2x80x94SO2-alkyl or xe2x80x94SO2-aryl wherein xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9csulfmylxe2x80x9d represents a group of the formula xe2x80x94SO-alkyl or xe2x80x94SO-aryl wherein xe2x80x9callylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl. benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9cesterxe2x80x9d means a group of formula xe2x80x94COO-alkyl, or xe2x80x94COO-aryl wherein xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9coxyesterxe2x80x9d means a group of formula xe2x80x94COO-alkyl, or xe2x80x94COO-aryl wherein xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9cetherxe2x80x9d means a group of formula alkyl-O-alkyl or alkyl-O-aryl or aryl-O-aryl wherein xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9camidoxe2x80x9d means a group of formula xe2x80x94CONH2 or xe2x80x94CONHalkyl or xe2x80x94CON(alkyl)2 or xe2x80x94CONHaryl or xe2x80x94CON(aryl)2 wherein xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferably alkyl has 1-4 carbon atoms and aryl has 6-10 carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term xe2x80x9coxyamidoxe2x80x9d xe2x80x9cmeans a group of formula xe2x80x94Oxe2x80x94CONH2 or xe2x80x94Oxe2x80x94CONHalkyl or xe2x80x94Oxe2x80x94CON(alkyl)2 or xe2x80x94O-CONHaryl or xe2x80x94CON(aryl)2 wherein alkylxe2x80x9d and xe2x80x9carylxe2x80x9d are defined above. Preferably alkyl has 1-5 carbon atoms and aryl has 6-8 carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
Preferably R1 is methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halogen group such as trifluoromethyl trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
Preferably R2, R3 and R4 are independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
Preferably R5 and R6 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl.
Preferably R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or the same substituted by at least a halo group such as trifluoromethyl, chlorophenyl.
Preferably R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same substituted by at least a halo group such as trifluoromethyl, chlorobenzyl or where X is xe2x80x94CN.
Unless otherwise stated, references herein to the compounds of general formula (A) either individually or collectively are intended to include geometrical isomers i.e. both Z (Zusammen) and E (Entgegen) isomers and mixtures thereof (racemates).
With respect to the asymmetric hydrogenation process described below, the best results have been obtained for the Z (Zusammen) and E (Entgegen) isomers of the compounds of formula (A) where R1 is methyl, R2 and R4 are H and X is xe2x80x94CONH2 or xe2x80x94COOMe or xe2x80x94COOEt or xe2x80x94COOH. Within this group, compounds wherein R3 is hydrogen, alkyl (especially propyl) or haloalkenyl (especially difluorovinyl) are particularly well suited.
An aspect of the invention concerns a process for preparing the compound having a general formula (A). This process includes the following reactions:
Compounds having a general formula (A), where X is xe2x80x94CONR5R6 or xe2x80x94COOR7 or xe2x80x94COR8 or CN, may conveniently be made by reaction of an xcex1-ketocarboxylic acid derivative of general formula (C) where R1 and X are described above, with a pyrrolidinone of general formula (D) where R2, R3, R4 are described above, according to the following scheme (1). 
Compounds having a general formula (A) where X is xe2x80x94COOR7 may conveniently be made by reaction of an xcex1-ketocarboxylic acid derivative of general formula (Cxe2x80x2) where X is xe2x80x94COOR7 with a pyrrolidinone of general formula (D) according to the following scheme (2). 
Suitable reaction conditions involve use of toluene under reflux. In the resulting compound (A), R7 may readily be converted from H to alkyl or from alkyl to H.
Derivatives of general formula (C) or (Cxe2x80x2) and pyrrolidones of general formula (D) are well known by the man of the art and can be prepared according to syntheses referred to in the literature, such as in xe2x80x9cHandbook of Heterocyclic Chemistryxe2x80x9d by A. Katrisky, Pergamon, 1985 (Chapter 4.) and in xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d by A. Katrisky and C. W. Rees, Pergamon, 1984 (Volume 4, Chapters 3.03 and 3.06).
Compounds of general formula (A) where X is xe2x80x94CONH2 or xe2x80x94CONR5R6 may conveniently be prepared by conversion of the corresponding acid (compound of formula (A) where X is CO2H) to the acid chloride with subsequent ammonolysis or reaction with a primary or secondary amine of the general formula HNR5R6. The following two schemes (3 and 4) describe such a process. 
These reactions are preferably performed using PCl5 to give an acid chloride followed by anhydrous ammonia or primary or secondary amine of the formula HNR5R6 to give the desired enamide amide.
Compounds of general formula (A) where X is xe2x80x94COOR7 may conveniently be made by conversion of the corresponding acid (compound (A) where X is COOH) obtained by Scheme (2) to the acid chloride with subsequent alcoholysis with the compound of formula R7xe2x80x94OH (alcohol) where R7 is defined above. (see Scheme 5) 
These reactions are preferably performed using PCl5 to give an acid chloride followed by alcoholysis with R7xe2x80x94OH to give the desired ester.
The conditions of the above reactions are well known by the man skilled in the art.
In another aspect the invention concerns the use of compounds of formula (A) as synthesis intermediates.
The compound of formula (A) where X is xe2x80x94CONH2 is of particular interest, as catalytic hydrogenation of this compound leads directly to Levetiracetam. Both the Z (Zusammen) and E (Entgegen) isomers of these compounds have been shown to undergo rapid and selective asymmetric hydrogenation to either enantiomer of the desired product. The representation of the bond joining the group R1 to the molecule denotes either a Z isomer or an E isomer As a particular example, the use of compounds (A) for the synthesis of compounds (B) may be illustrated according to the following scheme (6). 
wherein R1, R2, R3, R4 and X are as noted above.
Preferably, R1 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most preferably methyl, ethyl or n-propyl.
Preferably, R2 and R4 are independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, are each hydrogen.
Preferably, R3 is C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azido, each optionally substituded by one or more halogen, cyano, thiocyano, azido, allylthio, cyclopropyl, acyl and/or phenyl; phenyl: phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl furryl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
Preferably, X is xe2x80x94COOH or xe2x80x94COOMe or xe2x80x94COOEt or xe2x80x94CONH2; most preferably xe2x80x94CONH2.
The compounds of formula (B) may be isolated in free form or converted into their pharmaceuticaly acceptable salts, or vice versa, in conventional manner.
Preferred individual compounds among the compounds having the general formula (B) have the formulas (Bxe2x80x2),(Bxe2x80x3) and (Bxe2x80x2xe2x80x3). 
The compounds of formula (B) are suitable for use in the treatment of epilepsy and related ailments. According to another embodiment, the invention therefore concerns a process for preparing a compound having a formula (B) 
wherein R1, R2, R3, R4 and X are as noted above, via catalytic assymetric hydrogenation of the corresponding compound having the formula (A) as illustrated and defined above. Catalytic hydrogenation is described in many publications or books such as xe2x80x9cSynthxc3xa8se et catalyse asymxc3xa8triquesxe2x80x94auxiliaires et ligands chirauxxe2x80x9d Jacqueline Seyden-Penne (1994)xe2x80x94Savoirs actuel, interEdition/CNRS Editionxe2x80x94CH 7.1 xe2x80x9chydrogenation catalytiquexe2x80x9d page 287-300.
Unless otherwise stated, references herein to the compounds of general formula (B) either individually or collectively are intended to include geometrical isomers i.e. both Z (Zusammen) and E (Entgegen) isomers as well as enantiomers, diastereoisomers and mixtures of each of these (racemates).
Preferably, the process of the invention concerns the preparation of compounds of formula (B) in which R2 and R4 are hydrogen and X is xe2x80x94COOE or xe2x80x94COOMe or xe2x80x94COOEt or xe2x80x94CONH2 and R1 is methyl particularly those wherein R3 is hydrogen, alkyl (especially propyl) or haloalkenyl (especially difluorovinyl). Best results have been obtained with the process for preparing levetiracetam, compound of formula (B) in which R1 is methyl, R2 and R4 are hydrogen, R3 hydrogen, propyl or difluorovinyl and X is xe2x80x94CONH2.
Generally, this process comprises subjecting to catalytic hydrogenation a compound of formula (A) as described above. Preferably the compound of formula (A) is subjected to asymmetric hydrogenation using a chiral catalyst based on a rhodium (Rh) or ruthenium (Ru) chelate. Asymmetric hydrogenation methods are described in many publications or books such as xe2x80x9cAsymmetric Synthesisxe2x80x9d R. A. Aitken and S. N. Kilxc3xa9nyi (1992)xe2x80x94Blackie Academic and Professional or xe2x80x9cSynthesis of Optically active-Amino Acidsxe2x80x9d Robert M. Willimas (1989)xe2x80x94Pergamon Press.
Rh(I)-, and Ru(ti)-, complexes of chiral chelating ligands, generally diphosphines, have great success in the asymmetric hydrogenation of olefins. Many chiral bidentate ligands, such as diphosphinites, bis(aminophosphine) and aminophosphine phosphinites, or chiral catalyst complexes, are described in the literature or are commercially available. The chiral catalyst may also be associated to a counterion and/or an olefin.
Although much information on the catalytic activity and stereoselectivity of the chiral catalysts has been accumulated, the choice of the ligands, the chiral catalysts and reaction conditions still has to be made empirically for each individual substrate. Generally the Rh(I) based systems are mostly used for the preparation of amino acid derivatives, while the Ru(II) catalysts give good to excellent results with a much broader group of olefinic substrates. Chiral catalyst chelators which may be used in the present invention, are DUPHOS, BPPM, BICP, BINAP, DIPAMP, SKEWPHOS, BPPFA, DIOP, NORPHOS, PROPHOS, PENNPHOS, QUPHOS, BPPMC, BPPFA. In addition to this, supported or otherwise immobilised catalysts prepared from the above chelators may also be used in the present invention in order to give either improved conversion or selectivity, in addition to improved catalyst recovery and recycling. Preferred chiral catalyst chelators for use in the method of this invention are selected from DUPHOS or Methyl, Diethyl, Diisopropyl-DUPHOS (1,2-bis-(2,5-dimethylphospholano)benzenexe2x80x94U.S. Pat. No. 5,171,892), DIPAMP (Phosphine, 1,2-ethanediylbis ((2-methoxyphenyl)phenylxe2x80x94U.S. Pat. Nos. 4,008,281 and No 4,142,992), BPPM (1-Pyrrolidinecarboxylic acid, 4-(diphenylphosphino)-2-((diphenylphosphino)methyl)-, 1,1-dimethylethyl esterxe2x80x94Japanese patent No 87045238) and BINAP (Phosphine, (1,1xe2x80x2-binaphthalene)-2,2xe2x80x2-diylbis(diphenylxe2x80x94European patent No. 0 366 390).
The structures of these chelators are shown below. 
Preferred solvents for use in the method of this invention are selected from, tetrahydrofuran (THF), dimethylformamide (DMF), ethanol, methanol, dichloromethane (DCM), isopropanol (IPA), toluene, ethyl acetate (AcOEt).
The counterion is selected from halide (halogen(xe2x88x92)), BPh4(xe2x88x92) ClO4(xe2x88x92), BF4(xe2x88x92). PF6(xe2x88x92), PCl6(xe2x88x92), OAc(xe2x88x92), triflate (OTf(xe2x88x92)), mesylate or tosylate. Preferred counterions for use with these chiral catalysts are selected from OTf(xe2x88x92), BF4(xe2x88x92) or OAc(xe2x88x92).
The olefin is selected from ethylene, 1,3-butadiene, benzene, cyclohexadiene, norbomadiene or cycloocta-1,5-diene (COD).
Using these chiral catalysts, in combination with a range of counter-ions and at catalyst-substrate ratios ranging from 1:20 to 1:20,000 in a range of commercially available solvents it is possible to convert compounds of formula (A) into laevorotary or dextrorotary enantiomers of compounds of formula (B) having high % of enantiomeric excess (e.e.) and in excellent yield, and high purity. Moreover, this approach will use standard industrial plant and equipment and have cost advantages.
This asymmetric synthesis process will also be lower cost due to the avoidance of recycling or discarding the unwanted enantiomer obtained by a conventional synthesis process.
Best results have been obtained with the process for preparing (S)-xcex1-ethyl-2-oxo-1-pyrrolidine acetamide or (R)-xcex1-ethyl-2-oxo-1-pyrrolidineacetamide, wherein it comprises subjecting a compound of formula Axe2x80x2 in the form of a Z isomer or an E isomer to asynmmetric hydrogenation using a chiral catalyst according to the following scheme. 
In what follows, reference is made particularly to four compounds of formula (A) in which R1 is methyl, R2, R3 and R4 are hydrogen and,
for the compound hereinafter identified as precursor Al, X is xe2x80x94COOH;
for the compound hereinafter identified as precursor A2, X is xe2x80x94COOMe;
for the compound hereinafter identified as precursor A2xe2x80x2, X is xe2x80x94COOEt; and
for the compound hereinafter identified as precursor A3, X is xe2x80x94CONH2.
As will be appreciated by the skilled person, depending on the substitution pattern, not all compounds of general formula (A) and (B) will be capable of forming salts so that reference to xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d applies only to such compounds of general formulae (A) or (B) having this capability.
The following examples are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.